The tropomyosin receptor kinase (Trk) receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system (Huang E J, Reichardt L F (2003). Annu. Rev. Biochem. 72: 609-642) (incorporated herein by reference). The Trk receptor family comprises 3 transmembrane proteins referred to as TrkA, TrkB and TrkC receptors that are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and play an essential role in the physiology of development and function of the nervous system through activation by neurotrophins (Patapoutian, A. et al. (2001) Current Opinion in Neurobiology 11: 272-280) (incorporated herein by reference).
Trk kinase fusions have been described in multiple cancers including colorectal cancer, lung adenocarcinoma, salivary gland cancer, head and neck squamous cell cancer, glioblastoma multiforme, and thyroid cancer (Vaishnavi A, Le A T, Doebele R C (2015). Cancer Discov. 5 (1): 25-34; Bishop J A et al. J Surg Pathol. 2013 37(7):1053-7; Prasad M L et al. Cancer, 2016 Jan. 19; brenca M. et al. J Pathol 2016, 238(4): 543-9) (each of which is incorporated herein by reference). Trk kinase fusions have further fueled the development of pan-Trk inhibitor drugs for use in oncology. In accordance with the potential for Trk fusions to be used as molecular targets in cancer, Trk inhibition has been shown in vitro to inhibit the proliferation of cell lines expressing Trk fusions. Recent clinical study details strong clinical response to a Trk inhibitor by a sarcoma patient, and thus the patient could be rationally treated with a pan-Trk inhibitor drug (Robert C. Doebert et al. (2015) Cancer Discov. 5(10): 1049-1057) (Incorporated herein by reference).
Inhibitors of the Trk/neutrophin pathway have been demonstrated to be highly effective in numerous pre-clinical animal models of pain. Antagonistic NGF and TrkA antibodies have been shown to be efficacious in inflammatory and neuropathic pain animal models and in human clinical trials (Woolf, C. J. et al. (1994) Neuroscience 62, 327-331; Zahn, P. K. et al. (2004) J Pain 5, 157-163; McMahon5 S. B. et al., (1995) Nat. Med. 1, 774-780; Ma, Q. P. and Woolf, C. J. (1997) Neuroreport 8, 807-810; Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489-497; Lamb, K. et al (2003) Neurogastroenterol Motil 15, 355-361; and Jaggar, S. I. et al. (199) Br. J. Anaesth. 83, 442-448) (each of which is incorporated herein by reference). Also promising is the utility of Trk inhibitors in the treatment of inflammatory lung diseases such as asthma (Freund-Michel, V; et al., Pharmacology & Therapeutics (2008), 117(1), 52-76) (incorporated herein by reference), interstitial cystitis (Hu Vivian Y; et. al., J of Urology (2005), 173(3), 1016-21) (incorporated herein by reference), inflammatory bowel disease including ulcerative colitis and Crohn's disease (Di Mola, F. F., et al., Gut (2000), 46(5), 670-678) (incorporated herein by reference) and inflammatory skin diseases such as atopic dermatitis (Dou, Y. C., et. Al., Archives of Dermatological Research (2006), 298(1), 31-37) (incorporated herein by reference), eczema and psoriasis (Raychaudhuri, S. P. et. al., J of Investigative Dermatology (2004), 122(3), 812-819). Modulation of the neutrophin/Trk pathway also has been shown to have an effect in the etiology of neurodegenerative diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease (Sohrabji, et. al, Neuroendocrinology (2006), 27(4), 404-414) (incorporated herein by reference).
Despite this promising research, a need exists for compounds acting as Trk kinase mediators or inhibitors.